EP0389765B1 - Calcium antagonists - Google Patents

Calcium antagonists Download PDF

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Publication number
EP0389765B1
EP0389765B1 EP90102575A EP90102575A EP0389765B1 EP 0389765 B1 EP0389765 B1 EP 0389765B1 EP 90102575 A EP90102575 A EP 90102575A EP 90102575 A EP90102575 A EP 90102575A EP 0389765 B1 EP0389765 B1 EP 0389765B1
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represented
formula
treatment
methanol
composition according
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EP0389765A1 (en
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Albert A. Carr
Hsien C. Cheng
John M. Kane
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Aventis Pharmaceuticals Inc
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Merrell Dow Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/48—Nitrogen atoms not forming part of a nitro radical with acyclic hydrocarbon or substituted acyclic hydrocarbon radicals, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
    • C07D239/14—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/04—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
    • C07D245/02—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms not condensed with other rings

Definitions

  • the present invention is directed to a new class of cyclic guanidines and to their use as calcium antagonists. Another aspect of the invention is directed to the discovery of a new use for a group of known cyclic guanidines.
  • hypoglycemic agents Those compounds which are encompassed by the two provisos immediately above are known in the art as hypoglycemic agents. It has been discovered that these known compounds are also useful as calcium antagonists. These compounds are described in US-A 4,136,188 and US-A 4,174,401.
  • any reference to the compounds of Formula I should be considered as encompassing both those known cyclic guanidines as well as the new class of cyclic guanidines.
  • those portions of the specification in which methods are taught for making the compounds, their use as calcium antagonists, and means for formulating their pharmaceutical compositions are equally applicable to both the known cyclic guanidines and to the new class of cyclic guanidines encompassed by the present invention.
  • Calcium antagonists have been discovered to be useful in the treatment of a variety of disease states. They have been found to be useful in the treatment of cardiac arrhythmias, angina, depression, hypertension, epilepsy, and mania. They have also been found to exhibit a vasodilatory effect and therefore are useful in the treatment of congestive heart failure. More recently they have been discovered to be useful in preventing the phenomenon of calcium overload which is associated with reperfusion therapy. The compounds of Formula I are also useful for these therapeutic indications.
  • Some of the compounds of Formula I contain asymmetric centers. Any reference in this application to one of the compounds represented by Formula I is meant to encompass either a specific optical isomer or a mixture of enantiomers.
  • the specific optical isomers can be separated and recovered by techniques known in the art such as chromatography on chiral stationary phases or resolution via chiral salt formation and subsequent separation by selective crystallization.
  • All of the compounds of Formula I contain the guanidine moiety. This moiety may exist in any of the tautomeric forms depicted below.
  • the present invention should be considered as encompassing compounds existing in either of these tautomeric forms:
  • Ar and Ar1 can be independently represented by either a substituted or an unsubstituted phenyl ring. Both phenyl rings can be either substituted, unsubstituted, or only one of the phenyl rings may be substituted. If the phenyl ring is substituted, there can be up to 3 substitutions occurring on either phenyl ring. These substitutions can be the same or different. These substitutions can occur at any of the ortho, meta, or para positions.
  • the 1-position of the piperidino ring should be bonded to the diamino-substituted carbon of Formula I and the 4-position of the piperidino ring should be bonded to the diphenyl substituted carbon of Formula I.
  • the piperidino ring should remain unsubstituted otherwise.
  • A is represented by a piperazino ring
  • one of the nitrogen atoms in the piperazino ring should be bonded to the diamino substituted carbon of Formula I and the other nitrogen atom of the piperazino ring should be bonded to the diphenyl substituted carbon of Formula I.
  • the piperazino ring should remain otherwise unsubstituted.
  • Representative members of the new class of cyclic guanidines encompassed by Formula I include:
  • Representative members of known cyclic guanidines for which a new use has been discovered include:
  • the preferred compounds of Formula I include those in which Q is represented by (CH2)2, (CH2)3, (CH2)5 or A is represented by NH-CH2, NH-(CH2)2 or NH-(CH2)3; and both R and R1 are represented by hydrogen. These preferred compounds are represented by Formulas II and IIa:
  • the compounds of Formula I can be synthesized using techniques known in the art. One such technique is illustrated below.
  • a displacement reaction is conducted between a 2-methylthio-1,3-diazacycloalkane as described by Formula III and a diarylalkylamine as described by Formula IV below:
  • Q and R are as defined in Formula I.
  • R1, A, Ar and Ar1 are also as defined in Formula I.
  • the 2-methylthio-1,3-diazacycloalkane of Formula III is typically present as an acid addition salt.
  • Z can be represented by any suitable anion such as I ⁇ , Br ⁇ , Cl ⁇ , CF3SO3 ⁇ , or CH3SO3 ⁇ . Typically, Z is represented by I ⁇ .
  • non-reacting substituents appearing in both the 2-methylthio-1,3-diazacycloalkane of Formula III and the diarylalkylamine of Formula IV correspond to those appearing in the final product.
  • the desired cyclic guanidine is 2-(2,2-diphenylethylamino)-1,4,5,6-tetrahydropyrimidine
  • it can be produced by conducting a displacement reaction between an acid addition salt of 2-methylthio-1,4,5,6-tetrahydro-pyrimidine and 2,2-diphenylethylamine.
  • the displacement reaction is typically conducted at a temperature range of from 100°C to 170°C, for a period of time ranging from 10 minutes to 90 minutes.
  • the reaction is typically conducted neat. It can be conducted in an organic solvent such as, for example, ethanol or isopropanol.
  • organic solvent such as, for example, ethanol or isopropanol.
  • approximately equimolar quantities of the 2-methylthio-1,3-diazacycloalkane of Formula III and the diarylalkylamine of Formula IV are reacted together. A slight molar excess of either reactant is not deleterious to the reaction.
  • the cyclic guanidines of Formula I can be recovered from the reaction zone and purified by techniques well known in the art. Typically the product of the displacement reaction is dissolved in an alcohol such as methanol or isopropanol. The solution produced thereby is concentrated in order to produce a solid. This resulting solid is then redissolved in a solvent such as methanol or dichloromethane and neutralized with a base such as aqueous sodium hydroxide, thereby producing the free base of the cyclic guanidine.
  • a solvent such as methanol or dichloromethane
  • the cyclic guanidine can then be recovered by forming its hydrochloride acid addition salt and then causing the precipitation of this hydrochloride salt.
  • the hydrochloride acid addition salt of the cyclic guanidine can be formed by contacting the neutralized solution obtained above with a methanolic solution of HCl.
  • the hydrochloride salt of the cyclic guanidine can be precipitated from solution by a variety of techniques known in the art such as conducting an azeotropic distillation in the presence of 2-butanone or isopropanol. Typically the precipitate is collected by filtration and is then further purified by recrystallization from a solvent such as isopropanol or methanol/2-butanone. Other suitable solvents for this recrystallization will be apparent to those skilled in the art. Optionally further chromatographic purification techniques can be conducted.
  • the diarylalkylamines of Formula IV are known in the art as are their methods of preparation.
  • the 2-methylthio-1,3-diazacycloalkanes of Formula III can be made by techniques well known in the art.
  • One such technique comprises the methylation of a cyclic thiourea as described by Formula V in which Q and R are as defined in Formula I:
  • Q and R are as defined in Formula I:
  • the non-reacting substituents appearing in the cyclic thiourea of Formula V correspond to those appearing the 2-methylthio-1,3-diazacycloalkane of Formula III.
  • the methylation is typically accomplished by contacting approximately equimolar amounts of the cyclic thiourea of Formula V with methyl iodide. This methylation is typically conducted in methanol at a temperature range of from 10°C to 65°C, for a period of time ranging from 15 minutes to 2 hours.
  • the acid addition salt of the 2-methylthio-1,3-diazacycloalkane produced thereby can be recovered from the reaction zone by the addition of ether and collection of the precipitated product by filtration. It can be optionally purified by recrystallization from a solvent system such as methanol/ether.
  • the reaction between the diamine starting material of Formula VI and the carbon disulfide is typically conducted at a temperature range of from 0°C to 20°C for a period of time ranging from 0.5 hours to 3 hours.
  • the reaction is also typically conducted in an alcoholic solvent such as ethanol.
  • the diamine and the carbon disulfide are present in the reaction medium in approximately equimolar quantities. It is not necessary to purify the dithiocarbamate inner salt produced thereby, prior to its utilization in the thermolysis reaction.
  • the dithiocarbamate inner salt of Formula VII is then subjected to the thermolysis reaction described above which produces the cyclic ureas of Formula V.
  • This thermolysis reaction can be conducted either neat or in a solvent such as water. The reaction is typically conducted neat.
  • the thermolysis is accomplished by heating the dithiocarbamate to a temperature range of 100°C to 200°C and more preferably 130°C to 160°C, for a period of time ranging from 10 minutes to 60 minutes.
  • the cyclic thiourea of Formula V produced by the thermolysis reaction can be recovered and purified by techniques known in the art.
  • One suitable recovery technique is extraction with an organic solvent subsequent to the addition of water to the reaction zone.
  • the organic layer obtained thereby is typically concentrated and the resulting concentrate is subjected to recrystallization from a solvent such as ethanol.
  • the cyclic guanidines of Formula I can be synthesized by conducting a displacement reaction between the previously described diarylalkylamine of Formula IV and a 1,3-diazacycloalkane as described by Formula VIII in which Q and R are as described in Formula I and X is represented by either Cl or OCH3:
  • This displacement reaction may be conducted analogously to the displacement reaction between the methylthio-1,3-diazacycloalkane of Formula III and the diarylalkylamine of Formula IV which was discussed above.
  • the recovery and purification utilized with this alternative displacement reaction is not conducted in the same manner. Rather it is modified in the following manner.
  • the 1,3-diazacycloalkanes of Formula VIII are produced in the following manner. Initially a hydroxylamine as described by Formula IX in which Q and R are as defined in Formula I is subjected to a Lossen rearrangement: The Lossen rearrangement produces a cyclic urea as described by Formula X in which Q and R are also as defined above: The Lossen rearrangement is accomplished according to techniques known in the art. Typically the hydroxylamine is contacted with an excess of polyphosphoric acid for a period of time ranging from 10 minutes to 3 hours. The rearrangement is typically conducted at a temperature range of from 100°C to 200°C.
  • the cyclic urea of Formula X produced thereby is recovered and purified according to techniques known in the art. It is typically recovered by extraction with an organic solvent. The resulting organic layer is typically concentrated and subjected to recrystallization in a solvent such as ethanol.
  • the 1,3-diazacycloalkanes of Formula VIII in which X is represented by OCH3 can be obtained from a cyclic urea of Formula X in the following manner.
  • a cyclic urea of Formula X is contacted with an equimolar quantity of dimethylsulfate, (CH3)2SO4.
  • the reaction is typically conducted at a temperature range of from O°C to 100°C for a period of time ranging from 2 hours to 14 hours.
  • the 1,3-diazacycloalkanes of Formula VIII in which X is represented by Cl can be obtained by contacting a cyclic urea of Formula X with about an equimolar quantity of phosphorus oxychloride, (POCl3).
  • the reaction is typically conducted at a temperature range of from 20°C to 100°C for a period of time ranging from 2 hours to 14 hours.
  • the 1,3-diazacycloalkanes of Formula VIII can be recovered and purified by techniques known in the art. They can be recovered by extraction with an organic solvent after water has been added to the reaction zone. The resulting organic layer is typically concentrated and the resulting concentrate is recrystallized from a solvent system such as ethyl acetate/hexane.
  • the cyclic thioureas previously described by Formula V in which Q and R are as defined in Formula I can also be produced from the cyclic urea of Formula X. This is accomplished by reacting the cyclic urea of Formula X with a thionating agent such as Lawesson's Reagent for a period of time ranging from 0.5 hours to 14 hours. The reaction is typically conducted at a temperature range of from 20°C to 110°C in a solvent such as tetrahydrofuran or toluene. Once the cyclic thiourea of Formula V is formed, it can be recovered and purified by the method previously taught above. It can then be utilized to form the 2-methylthio-1,3-diazacycloalkane of Formula III in the manner taught above.
  • a thionating agent such as Lawesson's Reagent
  • the compounds of Formula I are calcium antagonists.
  • the protocol is based upon the fact that calcium ions increase the force of contraction of smooth muscle fibers.
  • the compounds are introduced into a tissue bath containing both smooth muscle fibers and calcium ions, and the effect the compounds have upon the force of contraction of the muscle fibers is measured.
  • the test is conducted in the following manner. Pieces of ileum, 2 cm in length, from male guinea pigs (200-400 g) are set up in isolated organ baths in Ca++-free K+ Tyrode's solution (in mM, NaCl 137, KCl 40, NaH2PO4 0.4, NaHCO3 11.9, glucose 5.5) and gassed with 95% O2, 5% CO2 at 37°C. Contractions are obtained by adding calcium chloride into the bath, and measured isotonically with a 1 g load. Cumulative dose-response curves of calcium chloride are obtained. Tissues are then washed and incubated with the test compounds for 20-25 minutes and then Ca++ concentration response curves re-established.
  • Ca++-free K+ Tyrode's solution in mM, NaCl 137, KCl 40, NaH2PO4 0.4, NaHCO3 11.9, glucose 5.5
  • Contractions are obtained by adding calcium chloride into the bath,
  • the preparations are stable for at least 5 hours and give reproducible dose-response curves to Ca++. Dose ratios are determined graphically at ED50 values from the Ca++ dose-response curve and Schild plots are constructed to determine pA2 value using inverse regression line analysis; O. Arunlakshana and H.O. Schild, Brit. J. Pharmacol . 14: 48-52, 1959. Alternatively, when only one concentration of an antagonist is used, pA2 values can be calculated according to the method of J. M. Van Rossum, Arch. Int. Pharmacodyn Ther. 143: 299-330, 1963.
  • the compounds of Formula I are calcium antagonists, they are effective in the treatment of a number of disease states. They are useful in the treatment of angina, hypertension, mania, epilepsy, depression, primary pulmonary hypertension, hyperurecemia, achalasia, asthma, Raynaud's phenomenon, and cardiac arrhythmias. The compounds also exhibit vasodilatory properties and thus are useful where such a physiological effect is desirable, such as in the treatment of congestive heart failure.
  • a compound of Formula I in an amount sufficient to treat the disease or condition (i.e. an antihypertensive amount, antianginal amount, antimanic amount, etc.). This quantity will be within the dosage range at which the compounds exhibit their calcium antagonistic effects.
  • the dosage range at which these compounds produce their calcium antagonist effects can vary widely depending upon the particular compound being administered, the particular disease or condition being treated as well as its severity, the patient, other underlying disease states the patient is suffering from, the route of administration, and other medications that may be concurrently administered to the patient.
  • the compounds will exhibit their calcium antagonistic properties at a dosage range of from 0.01 mg/kg of patient body weight/day to 100 mg/kg of patient body weight/day.
  • the compounds of the present invention may be administered by a variety of routes. They are effective if administered orally.
  • the compounds may also be administered parenterally (i.e. subcutaneously, intravenously, intramuscularly, or intraperitoneally).
  • the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions.
  • Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations.
  • the compounds of Formula I can be tabletted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate.
  • Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art.
  • the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a suspension.
  • suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin.
  • the pharmaceutical carrier may also contain preservatives, and buffers as are known in the art.
  • the compounds may also be incorporated into any inert carrier so that they may be utilized in routine serum assays, blood levels, and urine levels, according to techniques well known in the art.
  • the purpose of this example is to demonstrate the preparation of a known cyclic guanidine, 2-(1,1-diphenylmethylamino)imidazoline.
  • a flask containing a mixture of 2-methylthioimidazoline hydroiodide (7.40 g, 3.00 x 10 ⁇ 2 mole) and 1,1-diphenylmethylamine (5.50 g, 3.00 x 10 ⁇ 2 mole) was immersed in an oil bath which had been preheated to ca . 155°C. The mixture was stirred at between 150-160°C for 30 minutes. The resulting yellow glass was dissolved in minimal methanol. 2-Butanone was added and the solution was concentrated. After being allowed to stand in the freezer for several days, 5.70 g (50%) of the product hydroiodide was collected by filtration.
  • the purpose of this example is to demonstrate the preparation of one of the known cyclic guanidines, 2-(2,2-diphenylethylamino)-1-methylimidazoline.
  • a flask containing a mixture of 1-methyl-2-methylthioimidazoline hydroiodide (2.58 g, 1.00 x 10 ⁇ 2 mole) and 2,2-diphenylethylamine (1.97 g, 1.00 x 10 ⁇ 2 mole) was immersed in an oil bath which had been preheated to ca . 155°C.
  • the mixture was stirred at between 150-155°C for ca . 20 minutes.
  • the resulting yellow glass was treated with isopropanol and the solid was collected by filtration affording a colorless powder which was dissolved in methanol (20 ml).
  • the purpose of this example is to demonstrate the preparation of one member of the new class of cyclic guanidines as described by Formula I, 2-(2,2-diphenylethylamino)imidazoline.
  • a flask containing a mixture of 2-methylthioimidazoline hydroiodide (3.66 g, 1.50 x 10 ⁇ 2 mole) and 2,2-diphenylethylamine (2.96 g, 1.50 x 10 ⁇ 2 mole) was immersed in an oil bath which had been preheated to ca . 155°C. The mixture was stirred at between 150-160°C for 30 minutes. The resulting yellow glass was dissolved in methanol. Evaporation of the methanol gave a yellow oil which was dissolved in ethyl acetate. The solution was transferred to a separatory funnel where it was washed with 2N NaOH and saturated aqueous NaCl.
  • the purpose of this example is to demonstrate the preparation of one member of the new class of cyclic guanidines as described by Formula I, 2-(3,3-diphenylpropylamino)-1-methylimidazoline.
  • the purpose of this example is to demonstrate the preparation of one member of the new class of cyclic guanidines as described by Formula I, 2-(2,2-diphenylethylamino)-1,4,5,6-tetrahydropyrimidine.
  • a flask containing a mixture of 2,2-diphenylethylamine (5.92 g, 3.00 x 10 ⁇ 2 mole) and 2-methylthio-1,4,5,6-tetrahydropyrimidine hydroiodide (7.74 g, 3.00 x 10 ⁇ 2 mole) was immersed in an oil bath which had been preheated to ca . 155°C.
  • the reaction was stirred at between 150-168°C for 1.5 hours.
  • the resulting yellow glass was dissolved in methanol.
  • the methanol was evaporated and the resulting yellow oil was dissolved in dichloromethane. This solution was transferred to a separatory funnel where it was washed with 2N aqueous NaOH and saturated aqueous NaCl.
  • the purpose of this example is to demonstrate the preparation of one member of the new class of cyclic guanidines as described by Formula I, 2-(3,3-diphenylpropylamino)-1-methyl-1,4,5,6-tetrahydropyrimidine.
  • This material was dissolved in a two phase mixture of 5 molar aqueous NaOH (100 ml) and CH2Cl2 (100 ml). After stirring overnight, the CH2Cl2 layer was separated. The aqueous alkaline layer was extracted with CH2Cl2 (2x). The CH2Cl2 layers were combined, washed with H2O (2x), washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving a colorless foam which was dissolved in methanol (50 ml). The solution was cooled to 0°C before being treated with a methanolic solution of HCl.
  • the purpose of this example is to demonstrate the preparation of one member of the new class of cyclic guanidines as described by Formula I, 2-(2,2-diphenylethylamino)-1,4,5,6,7-pentahydro-1,3-diazepine.
  • This material was dissolved in a two phase mixture of 5 molar aqueous NaOH (100 ml) and CH2Cl2 (100 ml). After stirring overnight, the CH2Cl2 layer was separated. The aqueous alkaline layer was extracted with CH2Cl2 (2x). The CH2Cl2 layers were combined, washed with H2O, washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving a colorless foam which was dissolved in methanol (55 ml). The solution was cooled to 0°C before being treated with a methanolic solution of HCl.
  • the purpose of this example is to demonstrate the preparation of one member of the new class of cyclic guanidines as described by Formula I, 2-(2,2-diphenylethylamino)-1,4,5,6,7,8-hexahydro-1,3-diazocine.
  • the purpose of this example is to demonstrate the preparation of one member of the new class of cyclic guanidines as described by Formula I, 2-(3,3-diphenylpropylamino)-1,4,5,6,7,8-hexahydro-1,3-diazocine.
  • the purpose of this example is to demonstrate the preparation of one member of the new class of cyclic guanidines as described by Formula I, 2-(3,3-diphenylpropylamino)-1,4,5,6,7-pentahydro-1,3-diazepine.
  • the purpose of this example is to demonstrate the preparation of one member of the new class of cyclic guanidines as described by Formula I, 2-(2,2-diphenylethylamino)-1-methyl-1,4,5,6-tetrahydropyrimidine.
  • the purpose of this example is to demonstrate the preparation of one member of the new class of cyclic guanidines as described by Formula I, 2-(3,3-diphenylpropylamino)-1,4,5,6-tetrahydropyrimidine.
  • This material was dissolved in a two phase mixture of 5 molar aqueous NaOH (48 ml) and CH2Cl2 (44 ml). After stirring overnight, the CH2Cl2 layer was separated. The aqueous alkaline layer was extracted with CH2Cl2 (2x). The CH2Cl2 phases were combined, washed with H2O (2x), washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure. The concentrate was dissolved in methanol (60 ml) and the resulting solution was cooled to 0°C before being treated with a methanolic solution of HCl.
  • the purpose of this example is to demonstrate the preparation of one member of the new class of cyclic guanidines as described by Formula I, 2-(4,4-diphenylbutylamino)-1-methylimidazoline.
  • a flask containing 1-methyl-2-methylthioimidzoline hydroiodide (2.58 g,1.00 x 10 ⁇ 2 mole) and 4,4-diphenylbutylamine (2.25 g, 1.00 x 10 ⁇ 2 mole) was immersed in an oil bath which had been preheated to ca . 155°C.
  • the reaction was heated at between 150-160°C for 1 hour.
  • the resulting yellow glass was dissolved in methanol.
  • the methanol was evaporated at reduced pressure and isopropanol was added periodically with continued concentration until the solution became turbid. After standing, a colorless solid was collected by filtration.
  • This material was dissolved in a stirred, two phase mixture of 5 molar aqueous NaOH (56 ml) and CH2Cl2 (51 ml). After stirring overnight, the CH2Cl2 layer was separated. The aqueous alkaline layer was extracted with CH2Cl2 (2x). The CH2Cl2 layers were combined, washed with H2O (2x), washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated to a foam which was dissolved in methanol (40 ml). This solution was cooled to 0°C before being treated with a methanolic solution of HCl.
  • the purpose of this example is to demonstrate the preparation of one member of the new class of cyclic guanidines as described by Formula I, 2-(2,2-diphenylethylamino)-trans-3a,4,5,6,7,7a-hexahydro-1H-benzimidazole.
  • the solution was cooled to 0°C before being treated with a methanolic solution of HCl.
  • the methanol was evaporated at reduced pressure leaving a foam.
  • the foam was dissolved in methanol (10-15 ml) and 2-butanone was added.
  • the solution was then concentrated on the steam bath. When the temperature of the solution reached ca . 75°C a solid began to precipitate and the evaporation was stopped. After standing 2 hours the precipitate was collected by filtration affording a solid.
  • the purpose of this example is to demonstrate the preparation of one member of the new class of cyclic guanidines as described by Formula I, 2-(3,3-diphenylpropylamino)-trans-3a,4,5,6,7,7a-hexahydro-1H-benzimidazole.
  • the filtrate was evaporated at reduced pressure affording a foam which was dissolved in a stirred, two phase mixture of 5 molar aqueous NaOH (70 ml) and CH2Cl2 (65 ml). After stirring over the weekend, the CH2Cl2 layer was separated. The aqueous alkaline layer was extracted with CH2Cl2 (2x). The CH2Cl2 layers were combined, washed with H2O (2x), washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving an oil which was dissolved in methanol (43 ml).
  • the purpose of this example is to demonstrate the preparation of one member of the new class of cyclic guanidines as described by Formula I, 3-(2,2-diphenylethylamino)-2,5-dihydro-1H-2,4-benzodiazepine.

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EP90102575A 1989-02-10 1990-02-09 Calcium antagonists Expired - Lifetime EP0389765B1 (en)

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US30975089A 1989-02-10 1989-02-10
US309750 1989-02-10
US07/457,997 US5106845A (en) 1990-01-10 1990-01-10 Calcium antagonists
US457997 1999-12-09

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JP (1) JP2879918B2 (ko)
KR (1) KR0149165B1 (ko)
CN (1) CN1044813A (ko)
AT (1) ATE110367T1 (ko)
AU (1) AU621193B2 (ko)
CA (1) CA2009542C (ko)
DE (1) DE69011714T2 (ko)
ES (1) ES2063177T3 (ko)
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HU (1) HU204795B (ko)
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TW245719B (ko) * 1990-09-10 1995-04-21 Sterling Winthrop Inc
US5380721A (en) * 1990-09-10 1995-01-10 Sterling Winthrop Inc. Aryl-fused and hetaryl-fused-2,4-diazepine and 2,4-diazocine antiarrhythmic agents
US5314903A (en) * 1991-12-03 1994-05-24 Neurosearch A/S Benzimidazole compounds useful as calcium channel blockers
CA2104060A1 (en) * 1992-11-10 1994-05-11 Robert Ed Johnson Aryl-fused and hetaryl-fused-2,4-diazepine and 2,4-diazocine antiarrhythmic agents

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US4136188A (en) * 1976-06-25 1979-01-23 Daiichi Seiyaku Co., Ltd. Treatment of diabetes with 2-substituted-1,3-diazacyclic compounds
US4093726A (en) * 1976-12-02 1978-06-06 Abbott Laboratories N-(2-benzimidazolyl)-piperazines
US4174401A (en) * 1977-07-13 1979-11-13 Mcneil Laboratories, Incorporated 2-Benzhydrylimino-imidazolidines
US4243667A (en) * 1979-01-30 1981-01-06 Mcneil Laboratories, Incorporated 2-Benzhydrylimino-1,3-diazacarbocyclic compounds as inhibitors of gastric secretion
US4235894A (en) * 1979-01-30 1980-11-25 Mcneilab, Inc. 2-Benzhydrylimino-1,3-diazacarbocyclic compounds, compositions and methods of use
US4868181A (en) * 1986-08-04 1989-09-19 E. I. Du Pont De Nemours And Company 1,4-dihydropyridine derivatives with calcium agonist and alpha1 -antagonist activity
US5374637A (en) * 1989-03-22 1994-12-20 Janssen Pharmaceutica N.V. N-(3-hydroxy-4-piperidinyl)(dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzodioxin)carboxamide derivatives
FR2658823B1 (fr) * 1990-02-27 1992-04-30 Adir Nouveaux derives d'aminomethylpiperidine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent .

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DE69011714T2 (de) 1994-12-15
DE69011714D1 (de) 1994-09-29
EP0389765A1 (en) 1990-10-03
KR900012918A (ko) 1990-09-03
PT93106A (pt) 1990-08-31
ATE110367T1 (de) 1994-09-15
CN1044813A (zh) 1990-08-22
AU4932590A (en) 1990-08-16
JPH02282368A (ja) 1990-11-19
NO900646D0 (no) 1990-02-09
CA2009542A1 (en) 1990-08-10
KR0149165B1 (ko) 1998-10-15
FI900650A0 (fi) 1990-02-09
HU204795B (en) 1992-02-28
ES2063177T3 (es) 1995-01-01
HU900728D0 (en) 1990-04-28
CA2009542C (en) 2000-03-14
NZ232396A (en) 1991-07-26
JP2879918B2 (ja) 1999-04-05
HUT53089A (en) 1990-09-28
NO900646L (no) 1990-08-13

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